Noise-induced hearing loss is a major cause of acquired hearing deficits and one of the most frequent work-related disabilities in industrialized countries. The long term goal of this research is to understand the molecular mechanisms leading to noise-induced hearing loss. Based on exciting preliminary results on a signaling cascade initiated by energy depletion after noise exposure, the hypothesis is presented that transient energy depletion is an initial key factor in noise trauma. Transient energy depletion activates small GTPase pathways, which, in turn, lead to the destruction of F-actin in outer hair cells. Transient energy depletion also initiates mitochondria-mediated cell death, and blocks mTOR signaling pathways which normally serve as survival functions. In addition to the in-vivo studies, we are introducing a novel in-vitro model of energy depletion in an inner ear cell line to study specific aspects of the molecular pathways suspected in noise-induced hearing loss. The results of this project will lead to new insight into mechanisms of noise trauma. In addition, the results of this project may direct the design of novel interventions for the prevention of noise-induced hearing loss benefiting the quality of life of individuals and reducing health care costs.